TY - JOUR
T1 - An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling
AU - Impey, Soren
AU - Davare, Monika
AU - Lasiek, Adam
AU - Fortin, Dale
AU - Ando, Hideaki
AU - Varlamova, Olga
AU - Obrietan, Karl
AU - Soderling, Thomas R.
AU - Goodman, Richard H.
AU - Wayman, Gary A.
N1 - Funding Information:
We thank Jami Dwyer, Amir Bashar, and Kay Shi for technical assistance, Richard Mains for Kalirin-7 constructs and useful discusions and Gail Mandel for comments and suggestions. This work was supported by grants from the NIH and the Hope for Depression Research Foundation.
PY - 2010/1
Y1 - 2010/1
N2 - Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synaptic plasticity remain largely uncharacterized. We show here that the CREB- and activity-regulated microRNA, miR132, is induced during periods of active synaptogenesis. Moreover, miR132 is necessary and sufficient for hippocampal spine formation. Expression of the miR132 target, p250GAP, is inversely correlated with miR132 levels and spinogenesis. Furthermore, knockdown of p250GAP increases spine formation while introduction of a p250GAP mutant unresponsive to miR132 attenuates this activity. Inhibition of miR132 decreases both mEPSC frequency and the number of GluR1-positive spines, while knockdown of p250GAP has the opposite effect. Additionally, we show that the miR132/p250GAP circuit regulates Rac1 activity and spine formation by modulating synapse-specific Kalirin7-Rac1 signaling. These data suggest that neuronal activity regulates spine formation, in part, by increasing miR132 transcription, which in turn activates a Rac1-Pak actin remodeling pathway.
AB - Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synaptic plasticity remain largely uncharacterized. We show here that the CREB- and activity-regulated microRNA, miR132, is induced during periods of active synaptogenesis. Moreover, miR132 is necessary and sufficient for hippocampal spine formation. Expression of the miR132 target, p250GAP, is inversely correlated with miR132 levels and spinogenesis. Furthermore, knockdown of p250GAP increases spine formation while introduction of a p250GAP mutant unresponsive to miR132 attenuates this activity. Inhibition of miR132 decreases both mEPSC frequency and the number of GluR1-positive spines, while knockdown of p250GAP has the opposite effect. Additionally, we show that the miR132/p250GAP circuit regulates Rac1 activity and spine formation by modulating synapse-specific Kalirin7-Rac1 signaling. These data suggest that neuronal activity regulates spine formation, in part, by increasing miR132 transcription, which in turn activates a Rac1-Pak actin remodeling pathway.
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U2 - 10.1016/j.mcn.2009.10.005
DO - 10.1016/j.mcn.2009.10.005
M3 - Article
C2 - 19850129
AN - SCOPUS:72149098399
SN - 1044-7431
VL - 43
SP - 146
EP - 156
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 1
ER -